title: Mitochondrial fragmentation impairs insulin-dependent glucose uptake by modulating Akt activity through mitochondrial Ca2+ uptake.
abstract: Insulin is a major regulator of glucose metabolism, stimulating its mitochondrial oxidation in skeletal muscle cells. Mitochondria are dynamic organelles that can undergo structural remodeling in order to cope with these ever-changing metabolic demands. However, the process by which mitochondrial morphology impacts insulin signaling in the skeletal muscle cells remains uncertain. To address this question, we silenced the mitochondrial fusion proteins Mfn2 and Opa1 and assessed insulin-dependent responses in L6 rat skeletal muscle cells. We found that mitochondrial fragmentation attenuates insulin-stimulated Akt phosphorylation, glucose uptake and cell respiratory rate. Importantly, we found that insulin induces a transient rise in mitochondrial Ca(2+) uptake, which was attenuated by silencing Opa1 or Mfn2. Moreover, treatment with Ruthenium red, an inhibitor of mitochondrial Ca(2+) uptake, impairs Akt signaling without affecting mitochondrial dynamics. All together, these results suggest that control of mitochondrial Ca(2+) uptake by mitochondrial morphology is a key event for insulin-induced glucose uptake.
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiSCEMC, Facultad Ciencias Químicas y Farmacéuticas y Facultad Medicina, Santiago, Chile;
authors.forename: Andrea
authors.initials: A
authors.lastname: del Campo
authors.forename: Valentina
authors.initials: V
authors.lastname: Parra
authors.forename: César
authors.initials: C
authors.lastname: Vásquez-Trincado
authors.forename: Tomás
authors.initials: T
authors.lastname: Gutiérrez
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Morales
authors.forename: Camila
authors.initials: C
authors.lastname: López-Crisosto
authors.forename: Roberto
authors.initials: R
authors.lastname: Bravo-Sagua
authors.forename: Mario F
authors.initials: MF
authors.lastname: Navarro-Marquez
authors.forename: Hugo E
authors.initials: HE
authors.lastname: Verdejo
authors.forename: Ariel
authors.initials: A
authors.lastname: Contreras-Ferrat
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Troncoso
authors.forename: Mario
authors.initials: M
authors.lastname: Chiong
authors.forename: Sergio
authors.initials: S
authors.lastname: Lavandero
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000648:ultrastructure*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000648:ultrastructure*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000906:Antibodies; D007328:Insulin; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D051057:Proto-Oncogene Proteins c-akt; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat; C498811:Opa1 protein, rat; D005947:Glucose; D002118:Calcium
keywords: Mfn2; Opa1; calcium; insulin; mitochondrial fragmentation